tbuckley/cabot-search huggingface dataset:
Abstract 4932: The role of KB-S in treating pancreatic cancer
Authors: Sadia Noosrat Boshra, Kirpal Bisht, Mildred Acevedo-Duncan
Journal: Cancer Research (2023)

Abstract Pancreatic cancer remains one of the most lethal malignant cancers because the symptoms of this cancer do not exhibit until the disease progresses to an advanced stage. Late diagnosis may result in metastasis. When metastasis occurs, cancer can no longer be removed with surgery and therefore, requires treatment with FDA approved chemotherapeutic drugs or radiotherapy and they often fail to treat the disease. KB-S is a synthetic thymidine nucleoside analogue which is broadly used for the treatment of Human Immunodeficiency Virus (HIV). In this work, we explored the therapeutic potential of KB-S as an anticancer drug, with focused against pancreatic cancer. Our aim is to establish a connection between cellular kinase of KB-S and atypical protein kinase C (aPKC) to decipher signaling pathways. Pancreatic adenocarcinoma, ASPC-1 cell line was used for the study. Hemocytometer was used for cell counting for the dose response curve after treating with KB-S. Immunoprecipitation study was conducted using anti-PKC-iota beads. Western blot assay was performed using primary antibody PKC-zeta and a secondary antibody. Our results showed that KB-S decreases cell proliferation significantly on AsPC-1 cells over increasing the concentrations. KB-S decreased the proliferation by 20% for 0.5 µM (P≤ 0.09), 37% for 5 µM (P≤ 0.02), 44% for 10 µM (P≤ 0.01), 48% for 20 µM (P≤ 0.002) and 54% for 50 µM (P≤ 0.001) in AsPC-1 cells. We used the lowest concentration of 10 µM with significant inhibition for further experiments. We immunoprecipitated for PKC-ι and immunoblotted for PKC-ζ and the immunoblots showed that there is no association between PKC-ι and PKC-ζ in pancreatic cancer cell line (AsPC-1). But when we performed reverse immunoprecipitation, we found that there is an association between PKC-ι and PKC-ζ. Again, we immunoprecipitated for thymidine kinase and immunoblotted for PKC-ι and immunoblots showed that there is an association between thymidine kinase and PKC-ι. But when we did the reverse immunoprecipitation, we did not find any association between thymidine kinase and PKC-ι in pancreatic cancer cell line. Based on our preliminary studies, we report the anti-cancer effect of KB-S in treating a pancreatic cancer cell line leading to further future investigations. To the best of our knowledge, this is the first demonstration of therapeutic efficacy of KB-S against a cancer. Given that, KB-S is already approved by FDA for the treatment of HIV, it carries the potential to be repurposed for difficult to cure cancerous diseases such as pancreatic cancer. Citation Format: Sadia Noosrat Boshra, Kirpal Bisht, Mildred Acevedo-Duncan. The role of KB-S in treating pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4932.
Abstract 676: Neuro-oncology imaging mass cytometry panels enable spatial investigation of brain tumor microenvironment
Authors: Nick Zabinyakov, Qanber Raza, Christina Loh
Journal: Cancer Research (2023)

Abstract Brain neoplasms represent a complex form of cancer that is one of the most challenging to classify and treat. Over 120 different tumor subtypes originate from various parts of the central nervous system, which makes identifying the composition of the tumor microenvironment (TME) vital for early assessment of progression, treatment, and prevention. We developed high-plex proteomic analysis tools to thoroughly characterize the TME of both human and mouse brain tissues using Imaging Mass Cytometry™ (IMC™). IMC offers unprecedented insight into the TME by uncovering the spatial distribution of 40-plus distinct molecular markers without autofluorescence, facilitating the research of brain neoplasms. Here, we demonstrate the application of high-plex human and mouse neuro-oncology IMC panels on normal and tumor formalin-fixed paraffin-embedded brain tissues. A basic neurophenotyping panel was developed and used to customize the Maxpar® Human and Maxpar OnDemand™ Mouse Immuno-Oncology IMC Panel Kits. Human and mouse neuro-oncology panels provide deep phenotyping and characterization of brain TME composition. These neuro panels consist of cross-reactive clones and enable flexible panel design for brain-specific research goals, such as brain tumor classification, and assessment of neuronal inflammation, degeneration, and development. We applied the neuro-oncology panels on tissue microarrays (TMAs) containing a variety of human brain tumors and mouse glioblastoma and neuroblastoma tissues. Normal brain tissues were used for comparative analysis as controls. The Hyperion™ Imaging System was utilized to digitize images from the tissues followed by quantitative analysis to assess the cellular composition of normal and cancerous brain TME. We successfully identified major cell populations that make up human and mouse brain matter, such as neurons, astrocytes, microglia, and oligodendrocytes. Various tumor cell phenotypes, resident and infiltrating cells, and resting and activated microglia were detected in multiple tumor subtypes. Subsequent single-cell analysis provided a comprehensive and quantitative assessment of the brain TME in our samples. We classified the distinct states of neurons and quantified myeloid and lymphoid immune cell infiltration across normal, astrocytoma, and glioblastoma tissues. Empowered by high-plex neuro-oncology panels, IMC can accelerate brain tumor research and provide insights into the spatial complexity of neuronal neoplasms. Citation Format: Nick Zabinyakov, Qanber Raza, Christina Loh. Neuro-oncology imaging mass cytometry panels enable spatial investigation of brain tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 676.
Abstract 2593: A MYCN-independent mechanism mediating secretome reprogramming and metastasis in MYCN-amplified neuroblastoma
Authors: Hai-Feng Zhang, Alberto Delaidelli, Sumreen Javed, Busra Turgu, Christopher S. Hughes, Xiaqiu Yang, Michael Lizardo, Daniel Martinez, John M. Maris, Kristopher R. Bosse, Karla C. Williams, Poul H. Sorensen
Journal: Cancer Research (2023)

Abstract MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes gene expression independently of MYCN in MNA+ NB. We found that GREB1, as a crucial estrogen receptor (ER) regulatory factor, is highly expressed in MNA+ NB comparable to ER+ breast cancer. Among GREB1-regulated genes altered in MNA+ NB, we uncover that Myosin 1B (MYO1B) promotes aggressive features in MNA+ NB, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling uncover MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we found that MYO1B is also upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB. Citation Format: Hai-Feng Zhang, Alberto Delaidelli, Sumreen Javed, Busra Turgu, Christopher S. Hughes, Xiaqiu Yang, Michael Lizardo, Daniel Martinez, John M. Maris, Kristopher R. Bosse, Karla C. Williams, Poul H. Sorensen. A MYCN-independent mechanism mediating secretome reprogramming and metastasis in MYCN-amplified neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2593.
Abstract 5131: Pulmonary influenza infection promotes the awakening of dormant metastatic breast cancer cells
Authors: Shi Biao Chia, Bryan Johnson, Julio A. Aguirre-Ghiso, Mercedes Rincon, James DeGregori
Journal: Cancer Research (2023)

Abstract Breast cancer is the most common form of cancer and the second cancer-causing death in females. Although remission rates are high if detected early, survival rates drop substantially when breast cancer becomes metastatic. The most common sites of metastatic breast cancer are bone, liver and lung. Respiratory viral infections inflict illnesses on countless people. The latest pandemic caused by the respiratory virus, SARS-CoV-2, has infected more than 600 million worldwide, with documented COVID-related death upward of 1 million in the United States alone. Respiratory viral infections result in increased inflammation with immune cell influx and expansion to facilitate viral clearance. Prior studies have shown that inflammation, including through neutrophils, can contribute to dormant cancer cells reawakening and outgrowth. Moreover, inhibition of IL6 has been shown to decrease breast cancer lung metastasis in mouse models. However, how respiratory viral infections contribute to breast cancer lung metastasis remains to be unraveled. Using MMTV/PyMT and MMTV/NEU mouse models of breast cancer lung metastasis and influenza A virus as a model respiratory virus, we demonstrated that acute influenza infection and the accompanying inflammation and immune cell influx awakens and dramatically increased proliferation and expansion of dormant disseminated cancer cells (DCC) in the lungs. Acute influenza infection leads to immune influx and expansion, including neutrophils and macrophages, with increased proportion of MHCII+ macrophages in early time points, and a sustained decrease in CD206+ macrophages starting 6 days post-infection until 28 days after the initial infection. Additionally, we observed a sustained accumulation of CD4+ T cells around expanding tumor cells for as long as 28 days after the infection. Notably, neutrophil depletion or IL6 knockout reversed the flu-induced dormant cell expansion in the lung. Finally, awakened DCC exhibited downregulation of vimentin immunoreactivity, suggesting a role for phenotypic plasticity in DCC outgrowth following viral infection. In conclusion, we show that respiratory viral infections awaken and increase proliferation of dormant breast cancer cells in the lung, and that depletion of neutrophils or blocking IL6 reverses influenza-induced dormant cell awakening and proliferation. Citation Format: Shi Biao Chia, Bryan Johnson, Julio A. Aguirre-Ghiso, Mercedes Rincon, James DeGregori. Pulmonary influenza infection promotes the awakening of dormant metastatic breast cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5131.
Abstract 4143: Enhancing adaptive immune responses with telomerase-mediated telomere targeting therapeutics in hepatocellular carcinoma
Authors: Ann Marie Flusche, Jerry Shay, Ilgen Mender Ogunrinde
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and is the third leading cause of cancer-related deaths. In recent years, immune checkpoint inhibitors (ICIs) have improved treatment of solid tumors including HCC. However, due to low response rates with current standard of care immunotherapy and angiogenic inhibitors, there is an urgent need to develop new therapeutic strategies to improve the efficacy of immunotherapy against HCC. Our lab has shown that 6-thio-2’ deoxyguanosine (6-thio-dG), a telomerase-mediated telomere targeting agent, is incorporated into newly synthesized telomeres by telomerase and causes rapid telomere uncapping, thereby inducing telomere-associated DNA damage in cancer cells. These damaged DNA fragments can then lead to enhanced adaptive immune responses. In this study, we evaluated the therapeutic effects of 6-thio-dG in vitro and in vivo together with ICIs in liver tumors to determine whether combining immunotherapy with a telomere-targeting agent could serve as an effective strategy for HCC. To explore whether 6-thio-dG is effective in killing liver cancer cells, we ran cell viability and telomere dysfunction induced foci (TIF) assays to assess DNA damage on telomeres in vitro and compared tumor volumes of mice following 6-thio-dG monotherapy, immunotherapy, and sequential treatment of 6-thio-dG and immunotherapy in syngeneic mouse models. We observed that 6-thio-dG reduced cell viability and induced telomere dysfunction in a panel of human and mouse liver cancer cells. In addition, 6-thio-dG enhanced the therapeutic effect of immunotherapies in liver syngeneic mouse models. Overall, our findings show that the telomere-targeting anticancer agent 6-thio-dG inhibits HCC as a single monotherapy and/or sequential therapy together with immunotherapies. These results provide an experimental rationale for a potentially new immunochemotherapy strategy based on the administration of a telomere-targeting agent. Citation Format: Ann Marie Flusche, Jerry Shay, Ilgen Mender Ogunrinde. Enhancing adaptive immune responses with telomerase-mediated telomere targeting therapeutics in hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4143.
Abstract 4574: Long-term drug efficacy evaluation using stiffness-tunable scaffolds colonized by a three-dimensional tumor microenvironment
Authors: Elly De Vlieghere, Olivier De Wever
Journal: Cancer Research (2023)

Abstract Long-term drug evaluation heavily relies upon rodent models. Methods to reduce animal models in oncology may include three-dimensional cellular systems that take into account tumor microenvironment (TME) cell types and biomechanical properties. Innovative translational research is needed in low-grade serous ovarian cancer (LGSOC) in which the presence of oncogenic mutations in the RAS pathway likely suggest the opportunity to test targeted treatments. To address all these needs this study reports on an elastic polymer, to print a scaffold that mimics tissue relevant stiffness. Introduction of single cell suspensions from LGSOC patient-derived early passage cultures of cancer cells and cancer-associated fibroblast form heterocellular spheroids mimicking the growth ratio and spatial organization of the LGSOC TME. The resulting scaffold allows long-term (&amp;gt;40 days) follow-up and targeted compound evaluation confirmed the durable response to a drug combination. The drug-response results from this long-term in vitro model are compared with drug responses in an orthotopic LGSOC xenograft mouse model. In conclusion, the stiffness-tunable scaffolds colonized by a three-dimensional LGSOC TME allow long-term drug evaluation and can be considered as a valid alternative to reduce, replace and refine animal models in drug discovery. Citation Format: Elly De Vlieghere, Olivier De Wever. Long-term drug efficacy evaluation using stiffness-tunable scaffolds colonized by a three-dimensional tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4574.
Abstract 2331: Loss of LRRC15 in osteosarcoma cells disrupts extracellular matrix integration, intercellular communication, and differentiation
Authors: Sanjit Mukherjee, Ankit Jajoo, Jack Zhu, Marbin Pineda, Robert Walker, James Purcell, Lee J Helman, Paul S. Meltzer
Journal: Cancer Research (2023)

Abstract Background: Leucine rich repeat containing 15 (LRRC15) is a 581 amino acid type 1 transmembrane protein that contains 15 leucine rich repeats. Cysteine clusters flank the LRR domain that functions as the collagen binding domain. LRRC15 has been found to be upregulated during osteogenic differentiation of mesenchymal stem cells, induced by TGFβ, and highly expressed in multiple solid tumors, notably in osteosarcoma (1). Antibody drug conjugates targeting LRRC15 have shown promising activity in pre-clinical studies (2). Results: To investigate the function of LRRC15 in the osteosarcoma microenvironment, we generated inducible shRNA knockdown (KD) derivatives targeting 3’UTR and ORF regions of LRRC15 of four osteosarcoma cell lines. Using these models, we characterized the biological properties of LRRC15 knockdown under 2-D and 3-D growth conditions. We found that LRRC15 KD in 2-D culture resulted in reduced adhesion to extracellular matrix (ECM) components and impaired cell migration. In 3-D spheroid culture, LRRC15 KD severely impacted scaffold-free spheroid compaction and invasion of spheroids embedded in Matrigel. Dysregulation of multiple ECM, cell adhesion and communication pathways were revealed by transcriptomic analysis from samples collected at time points during the LRRC15 KD. Of interest, several key transcription factors including RUNX2, CTNNB1, and SP7 were downregulated in LRRC15 deficient cells. Conclusion: Our comprehensive results establish the importance of LRRC15 as a critical cell-adhesion molecule essential for the maintenance of the osteogenic intercellular communication, invasion and differentiation revealing novel aspects of osteosarcoma cell-biology. Reference:1.Purcell JW, Tanlimco SG, Hickson J, Fox M, Sho M, Durkin L, et al. LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody-Drug Conjugates. Cancer Res 2018;78:4059-4072.2.Slemmons KK, Mukherjee S, Meltzer P, Purcell JW, Helman LJ. LRRC15 antibody-drug conjugates show promise as osteosarcoma therapeutics in preclinical studies. Pediatr Blood Cancer 2020:e28771. Citation Format: Sanjit Mukherjee, Ankit Jajoo, Jack Zhu, Marbin Pineda, Robert Walker, James Purcell, Lee J Helman, Paul S. Meltzer. Loss of LRRC15 in osteosarcoma cells disrupts extracellular matrix integration, intercellular communication, and differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2331.
Abstract 2086: ISCVAM, an Interactive Single Cell Visual Analytics for Multiomics, accelerates the identification of novel rare cell populations
Authors: Thanh N. M. Nguyen
Journal: Cancer Research (2023)

Abstract BACKGROUND Emergent single cell technologies have accelerated the discovery of rare cell populations and characterization of complex tumor microenvironment (TME). We developed an Interactive Single Cell Visual Analytics for Multiomics, ISCVAM, a bioinformatics infrastructure to integrate and visualize high-dimensional sparse multiome single cell data. METHODS We built an interactive tool, ISCVAM with react.js for the web frontend, and node.js in the backend, with a data bridge to portable HDF5 storage. Commonly used R packages including Seurat, Signac, SingleR, and scType, were used offline for data processing and analyses. We investigated cell populations using two Multiome datasets for proof of principle:1) ~22K cells from the matched pairs of sorted CD8+Tissue resident memory (TRM) and recirculating (ReCir) T cells from 4 ovarian cancer patients in (Anadon, Yu et al. 2022) and 2) ~11K cells from a PBMC sample (from 10X Genomics). RESULTS ISCVAM enables users to investigate both user-defined markers in multiple modalities (RNA and ATAC) individually and jointly (through weighted nearest neighbor), in different dimension reduction projections and on multiple panels. It also allows discovery of novel signatures of unidentified cell populations using unsupervised clustering algorithms in multiple resolutions. Using the paired TRM and ReCir samples from a single patient as the discovery set, ISCVAM identified a small cluster of mucosal-associated invariant T (MAIT) cells with unique gene and open chromatin peak profiles in both samples (2.18% of the ReCir T cells and 1.50% of the TRM T cells), which was not reported in the original study. Using the identified signature (with SLC4A10, TLE1 and their linked peaks), the MAIT cells were observed in remaining 6 ovarian samples (5.39 ±4.05% cells in 3 ReCir samples and 1.05 ± 1.02% cells in 3 TRM samples) from the same study. The markers are robust and also validated in an independent PBMC 10X Genomics dataset. CONCLUSION The tool ISCVAM enables the discovery of rare immune cell populations by integrating transcriptional and epigenic profiles simultaneously at multiple resolutions. This information rich tool with multiple panels and modalities with high interactivity enables rapid identification of rare cell populations. This will accelerate the understanding of complex TME in cancer research. Citation Format: Thanh N. M. Nguyen. ISCVAM, an Interactive Single Cell Visual Analytics for Multiomics, accelerates the identification of novel rare cell populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2086.
Abstract 5178: Humanized OX40/OX40L mice as a tool for evaluating novel therapeutics
Authors: Chonghui Liu, Jiawei Yao, Xiaofei Zhou, James Jin, Zan Zhang
Journal: Cancer Research (2023)

Abstract The use of immune-competent mouse models that express target human genes provide a promising preclinical platform aimed at developing novel immunotherapies. Emerging immunotherapies include targeting OX40 and OX40 ligand (OX40L), which can lead to enhanced T cell activation, proliferation, and effector function. Blocking the OX40/OX40L pathway improves autoantigen-specific T cell responses and decreases immunocompetence across several autoimmune diseases. To explore the potential of OX40 and OX40L antibody efficacy studies, we developed double humanized B-hOX40/hOX40L mice by replacing the extracellular domain sequences of murine Ox40 and Ox40l with the corresponding human sequences. We validated human OX40L gene expression by RT-PCR and OX40/OX40L protein expression by flow cytometry in B-hOX40/hOX40L mice. Additionally, percentages of splenic, blood, and lymph node immune cells were similar between B-hOX40/hOX40L and wild-type C57BL/6 mice. Altogether, this data demonstrates that B-hOX40/hOX40L mice are suitable for in vivo efficacy studies using anti-human OX40 and OX40L antibodies. Citation Format: Chonghui Liu, Jiawei Yao, Xiaofei Zhou, James Jin, Zan Zhang. Humanized OX40/OX40L mice as a tool for evaluating novel therapeutics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5178.